Poster Presentation First Malaria World Congress 2018

Characterisation of the malaria parasite’s ‘multidrug resistance protein 1' in Xenopus laevis oocytes   (#340)

Sashika N Richards 1 , Sarah H Shafik 1 , Adele M Lehane 1 , Richard Callaghan 1 , Rowena E Martin 1
  1. Research School of Biology, The Australian National University, Canberra, ACT, Australia

Polymorphisms in the Plasmodium falciparum ‘multidrug resistance protein 1’ gene (pfmdr1) alter the parasite’s susceptibility to diverse pharmacons, including many antimalarial drugs [1-4].  Aside from its role in drug resistance, PfMDR1 fulfils an essential physiological role in the parasite, the nature of which is currently unknown.  PfMDR1 is a putative ABC transporter – i.e., a pump that expends ATP to move solutes against their electrochemical gradients – and is a homologue of the human P-glycoprotein (also known as HsMDR1).  HsMDR1 is expressed at both the plasma and lysosomal membranes of cancer cells, where it confers multidrug resistance by effluxing drugs out of the cytoplasm and thus away from their targets [5-6].  PfMDR1 is likewise located at the parasite’s plasma membrane as well as at the membrane of a lysosomal-type compartment known as the digestive vacuole (DV) [7].  The DV is the site of action, accumulation, and/or activation of many antimalarials, but it is unclear how PfMDR1 modulates the parasite’s susceptibility to these drugs.  Previous attempts to express PfMDR1 in heterologous systems have (1) resulted in exceedingly low transport signals with very poor signal-to-background ratios [8], (2) not permitted direct measurements of drug transport [9-11], and/or (3) have been retracted [12].  Furthermore, it is not understood why polymorphisms in pfmdr1 that increase the parasite’s resistance to one antimalarial (e.g., chloroquine) simultaneously render the parasite hypersensitive to another antimalarial (e.g., lumefantrine).  This phenomenon, which is known as ‘collateral sensitivity’, could be exploited to combat the emergence and spread of drug resistance.  We have succeeded in expressing PfMDR1 and HsMDR1 in Xenopus oocytes, achieving robust and reproducible heterologous systems for the detailed characterisation of these proteins.  An assessment of the abilities of clinically-relevant isoforms of PfMDR1 to transport chloroquine and lumefantrine, and of HsMDR1 to transport the anticancer drug vinblastine, will be presented.

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